Dissolving microneedles for nucleic acid delivery: A systematic search, review, and data synthesis

Dissolving microneedles deliver many classes of nucleic acids, overcoming susceptibility to enzymatic cleavage and poor intracellular delivery. Understanding the impact of microneedle formulation on nucleic acid therapeutic efficacy is critical for clinical translation. Here, we performed a systematic search to identify preclinical dissolving microneedle studies that deliver nucleic acid therapeutics including aptamers, DNA enzymes, mRNA, miRNA, plasmid DNA, recombinant viral vectors, and siRNA. This review quantitatively synthesizes preclinical data to identify correlations between microneedle form and function. Factors such as polymer molecular weight and incorporation of a nucleic acid carrier strongly influence mechanical and biological properties, while other design parameters allow for more flexibility. Altogether, 83 % of studies show equivalent or superior efficacy to existing nucleic acid administration routes including topical, subcutaneous, and intramuscular administration. Data especially supports the use of dissolving microneedles for viral and cancer vaccine applications, with a growing body of work exploring their utility for gene silencing. Nonetheless, several knowledge gaps remain. Emerging nucleic acid carrier chemistries that retain efficacy with improved toxicity profiles will define the next generation of formulations. Plasmid DNA and viral vectors show excellent long-term stability in dissolving microneedles, but further characterization is needed for long RNA transcripts. Finally, future work could explore the potential for non-dermal administration routes, as well as co-delivery of nucleic acids with small molecules to leverage synergistic effects. STATEMENT OF SIGNIFICANCE: This review comprehensively, critically, and quantitatively synthesizes preclinical dissolving microneedles for nucleic acid delivery. This approach identifies empirically supported correlations between microneedle form and function, highlighting evidence-based best practices and remaining challenges. The form-function relationships identified in this review will be valuable to those within the immediate microneedle field, as well as more broadly to audiences interested in nucleic acid therapeutics, drug delivery systems, microfabrication, and delivery strategies for low resource settings.